Leukocyte adhesion deficiency type I (LAD1) is a rare and often fatal primary immunodeficiency. It is caused by autosomal recessive mutations in the gene ITGB2, which encodes CD18 (the common ?2 subunit) of the ?2 family of integrin cell adhesion molecules that are specifically expressed on cells of hematopoietic origin like leukocytes. As a result of decreased function of ?2 integrins, leukocytes cannot extravasate from the vasculature and patients suffer from severe life threatening and recurrent non-pustular infections of the soft tissue including skin, mucosal membranes, and intestinal track. Hematopoietic stem cell transplantation is curative, but it is not without significant risk. In more moderate forms of the disease, integrin ?2 expression is characterized as being between 2 ? 30% of normal levels. An intriguing approach to overcoming the adhesion defects found in moderate LAD1 patients would be to directly activate ?2 integrins, like ?L?2, so that even low levels of this integrin would be sufficient to support essential leukocyte functions. Scientists at the Texas Heart Institute have developed a library of small molecule compounds that can directly bind and activate integrin cell adhesion receptors including the integrin ?L?2. These compounds are currently licensed to 7 Hills Pharma and are being developed for immuno-oncology (IO) indications as they can stimulate the immune system and synergize with checkpoint blockade therapies like anti-CTLA-4 and anti-PD(L)1. However, there is a clear opportunity to leverage these compounds as a treatment strategy to activate integrins like ?L?2 and directly target the cause of LAD1. In this phase I SBIR proposal, we will test the hypothesis that activation of ?2 integrins with small molecule compounds can overcome the adhesion defects seen in leukocytes of LAD1 patients, and in an animal model of moderate LAD1. In proposed aims we will screen over 500 integrin activating compounds, from 5 structural classes, to identify potent ?2 integrin activators. Representative compounds from each structural class will then be tested against a panel of mutations identified from moderate LAD1 patients. In vivo proof-of-concept experiments will be performed by testing integrin activating compounds in acute inflammatory responses in the CD18hypo mouse, which mimics moderate LAD1. Lastly, pharmacodynamic models of compound activity will be developed to inform future clinical development. The goal of this drug development program is the development of a safe and effective orally available treatment for patients with moderate to severe LAD1, an orphan disease indication for which there are no effective treatments outside of bone-marrow transplantation.